RU2292344C2 - Derivatives of pyridylcyanoguanidines and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyridylcyanoguanidines of the general formula (I):

or their pharmaceutically acceptable salts wherein 1 means hydrogen atom; X means hydrocarbon (C₁-C₁₂)-biradical; Y means a bond or oxygen atom (O); Z means 5-10-membered aromatic heterocyclic radical optionally substituted with hydroxy-group under condition that R1 is not bound to nitrogen atom in pyridyl ring. Compounds of the formula (I) and their salts possess antiproliferative activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 7 ex

Description

The present invention relates to new pyridylcyanoguanidine drugs and pharmaceutical compositions containing them, as well as their use in the manufacture of medicines.

Initially, it was discovered that pyridylcyanoguanidines, such as pinacidyl (N-1,2,2-trimethylpropyl-N'-cyano-N "- (4-pyridyl) guanidine) open potassium channels, after which they were developed as antihypertensive drugs. of the pinacidyl side chain to longer side chains containing aryl leads to a decrease in the antihypertensive activity of such compounds, however, it was found that the compounds thus obtained, on the other hand, have antitumor activity when administered orally in a rat model bearing th ascites tumors Yoshida (Yoshida ascites tumours).

Various classes of pyridyl cyanoguanidines with antiproliferative activity are disclosed, for example, in 660823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561. Structure-activity relationships (SARs) for such compounds are described in C. Schou et al., Bioorganic and Medicinal Chemistry Letters 7 (24), 1997, pp. 3095-3100, where the antiproliferative effect of a number of pyridylcyanoguanidines was analyzed in vitro on various cell lines of human lung and breast cancer, as well as on normal human fibroblasts.

Then P-J V Hjarnaa et al., Cancer Res. 59, 1999, pp. 5751-5757, published the test results of a particular cyanoguanidine compound, namely N- (6- (4-chlorophenoxy) hexyl) -N'-cyano-N "- (4-pyridyl) guanidine, in in vitro and in vivo assays. the compound has an in vitro activity comparable to that of cytostatic agents, daunorubicin and paclitaxel, but it exhibits much lower antiproliferative activity on normal human endothelial cells In vivo assays using nude mice that transplanted human tumor cells with union demonstrates significant antitumor activity, as well as in tumor cells that are resistant to conventional anti-cancer drugs such as paclitaxel.

For the successful use of the drug, a reasonable ratio of factors such as activity, bioavailability, toxicity, level of side effects, solubility, etc., which occurs in the case of advanced drugs based on cyanoguanidines, is necessary.

The inventors of the present invention have discovered that novel pyridyl cyanoguanidine compounds containing a heterocyclic radical have unusually high antiproliferative activity.

Accordingly, this invention relates to compounds of formula I

where R1 is hydrogen, halogen or one or more linear or branched, saturated or unsaturated C _l-6 hydrocarbon radicals optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarbonylamino, sulfo, aminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy, dihydroxyphosphinoyloxy or phosphono;

X is a linear or branched, saturated or unsaturated C _l-12 hydrocarbon diradical, optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, amino, aminoalkyl, aminocarbonyl, alkylcarbonylamino, sulfonamino, sulfonamino, hydroxysulfonyloxy, dihydroxyphosphinoyloxy or phosphono;

Y is a bond, O, C (O), S, S (O), S (O) ₂ , C (O) O, NH, C (O) NH, OC (O) or NHC (O);

Z represents an aromatic or nonaromatic heterocyclic radical having 5-12 ring atoms optionally substituted with halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl, aminoalkyl, or a linear or branched, saturated or unsaturated C _l-4 hydrocarbyl group optionally substituted with halogen, hydroxy, cyano, nitro, alkoxy, alkoxycarbonyl, alkylcarbonyl, formyl or aminoalkyl;

provided that R _{1 is} not attached to the nitrogen atom in the pyridyl ring;

as well as their pharmaceutically acceptable salts, solvates, hydrates, N-oxides and prodrug forms.

The invention also relates to the use of a compound of formula I in therapy and to pharmaceutical compositions comprising a compound of formula I.

The invention also relates to methods for treating or preventing diseases, comprising administering to the patient an effective dose of a compound of formula I.

In addition, this invention also relates to the use of compounds of formula I in the manufacture of pharmaceuticals.

In the context of the present invention, the term "hydrocarbon" means a fragment comprising only hydrogen and carbon, preferably including 1-18, for example 1-12, for example 1-6, carbon atoms. Examples of said hydrocarbon include methane, ethane, ethene, ethine, butane, butene, butine, isobutane, tert-butane, hexane, 1,3-dimethylhexane, octane, octene, nonin, dodecane, dodecene, etc. The corresponding radical or diradical is a fragment resulting from the removal of one or two hydrogen atoms from a hydrocarbon, respectively.

The term "heterocyclic radical" means monocyclic rings containing 1-3 heteroatoms selected from N, O and S, and fused bicyclic rings including 1-4 heteroatoms from the above. Examples include thienyl, furyl, pyranyl, isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, indolizinyl, purinyl, quinolyl, naphthyridinyl, tsinnonilil, chromanyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, oxazinyl, tetrahydrofuranyl, oxazolidinyl, tetrahydropyranyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, benzimidazolyl and benzofuranyl.

The term “halogen” means fluoro, chloro, bromo and iodo.

The term "pharmaceutically acceptable salt" means salts resulting from the interaction of compounds of formula I, including acidic or basic groups, with suitable bases or acids, respectively. Examples of such acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, acetic, phosphoric, lactic, maleic, phthalic, citric, propionic, benzoic, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, and tartaric acids. Examples of such bases are potassium hydroxide, sodium hydroxide, ammonia and amines.

The term “solvate” refers to particles resulting from the interaction of a compound, in this case, a compound of formula I, with a solvent, for example alcohol, glycerin or water, where these particles exist in solid form. If the solvent is water, the solvate is called hydrate.

The term “N-oxide” means, for example, the pyridyl-N-oxide derivatives of the compounds of this invention. Such compounds can be prepared by oxidation of N pyridyl with a suitable oxidizing agent, for example 3-chloroperbenzoic acid, in an inert solvent, for example dichloromethane.

The term “alkyl” means mono radicals derived from alkanes, preferably containing 1-8 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and cyclohexyl.

The term “alkoxy” means a radical of the formula —OR, wherein R is alkyl, as defined above.

The term “alkoxycarbonyl” means a radical of the formula —C (O) —OR, where R is alkyl, as defined above.

The term “alkylcarbonyl” means a radical of the formula —C (O) —R, where R is alkyl, as defined above.

The term “aminoalkyl” means a radical of the formula —R — NR ′ ₂ , where R is alkyl, as defined above, and each R ′ independently is alkyl, as defined above, or hydrogen.

The term “aminocarbonyl” means a radical of the formula —C (O) —NR ′ ₂ , where each R ′ independently is alkyl, as defined above, or hydrogen.

The term “aminosulfonyl” means a radical of the formula —S (O) ₂ —NR ′ ₂ , wherein each R ′ independently is alkyl, as defined above, or hydrogen.

The term “alkylsulfonylamino” means a radical of the formula N (R ′) S (O) ₂ —R, where R is alkyl as defined above and each R ′ independently is alkyl as defined above or hydrogen. The term “amino” denotes a radical of the formula —NR ′ ₂ , where each R ′ independently is alkyl, as defined above, or hydrogen.

The term "prodrug" means a derivative of an active compound that does not possess, or does not necessarily have, the physiological activity of the active compound, but which, when administered in a prodrug form, can undergo enzymatic cleavage in vivo, such as hydrolysis, to release the active compound. Obtaining a prodrug form of the compounds of the present invention is disclosed in international patent application PCT / DK01 / 00750.

In a preferred embodiment of the invention, R1 is hydrogen, halogen, or one or more linear or branched, saturated or unsaturated C _1-6 hydrocarbon radicals;

X is a linear or branched, saturated or unsaturated C _1-12 hydrocarbon diradical;

Y is O or C (O);

Z denotes an aromatic or non-aromatic heterocyclic radical containing 5-10 atoms in the cycle.

In a further preferred embodiment of the invention, R1 is hydrogen;

X is a linear C _5-10 hydrocarbon radical;

Y is O;

Z denotes an aromatic or non-aromatic heterocyclic radical containing 5-10 atoms in the cycle.

In another preferred embodiment, Z is selected from the group consisting of pyridyl, imidazolyl, quinolyl or pyrimidinyl.

Specific examples of compounds of formula I include

N- [6- (3-pyridyloxy) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine;

N- [6- (1-imidazolyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine;

N- [6- (2-Quinolyloxy) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine;

N- [6- (3-pyridyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine;

N- [6- (3-Quinolyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine;

N- [6- (5-pyrimidinyl) -1-hexyl] -N'-cyano-N "- (4-pyrididyl) guanidine.

Moreover, it was found that compounds selected from the group consisting of

3- [6- (N-tert-butoxycarbonylamino) -1-hexyloxy] pyridine;

3- [6-amino-1-hexyloxy] pyridine hydrochloride;

3- [6-amino-1-hexyloxy] pyridine;

1- [6- (N-tert-butoxycarbonylamino) -1-hexyl] imidazole;

1- (6-amino-1-hexyl) imidazole hydrochloride;

1- (6-amino-1-hexyl) imidazole;

2- [6- (N-tert-butoxycarbonylamino) -1-hexyloxy] quinoline;

2- (6-amino-1-hexyloxy) -quinoline;

can be used in the preparation of compounds of formula I.

Compounds of formula I can be prepared by reacting a compound of formula II where R1 is as defined in formula I with a compound of formula III where X, Y and Z are as defined in formula I, see Scheme.

The reaction can be carried out in a suitable solvent, such as pyridine, optionally in the presence of a tertiary amine, such as triethylamine, and a catalyst, such as 4- (N, N-dimethylamino) pyridine, and at a temperature in the range from room temperature to 100 ° C . During the reaction, R1, X, Y and Z may temporarily contain suitable protecting groups.

The compounds of formulas II and III are known from the literature or can be obtained using methods well known to specialists in this field.

In another embodiment, the thiourea of formula IV, which contains the same substituents as defined for formula (I) and optionally temporarily protected, is reacted with one or more equivalents of N, N'-dicyclohexylcarbodiimide (DCCD) and cyanamide in an inert solvent , such as acetonitrile, at a temperature exceeding room temperature, with the formation of the compounds of formula I, see scheme. Compounds of formula IV can be prepared using methods well known to those skilled in the art.

Pharmaceutical Compositions

In another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula I. Compositions of the present invention, both for use in veterinary medicine and for the treatment of humans, include the active ingredients in combination with pharmaceutically acceptable carrier (s) and optionally with another therapeutic ingredient (s). The carrier must be “acceptable” in the sense that it must be compatible with the other ingredients of the compositions and not adversely affect the recipient.

Typically, the active ingredient is 0.1-100 wt. % by weight of the composition. Typically, a single dose of the composition contains from 0.07 mg to 1 g of a compound of formula I.

The term "single dose" means a single, that is, a single dose that can be administered to the patient and which can be easily processed and packaged, while it remains physically and chemically stable single dose containing either the active substance as such or its mixture with solid or liquid pharmaceutical diluents or carriers. Compositions include, for example, forms suitable for oral (including sustained or controlled release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous), transdermal, ophthalmic, local, nasal or buccal administration.

Compositions can usually be presented in unit dosage form and can be prepared using any of the methods well known in the pharmaceutical art, for example, as disclosed in Remington, The Science and Practice of Pharmacy, 20th ed., 2000. All methods include a mixing step. an active ingredient with a carrier, which consists of one or more auxiliary ingredients. Basically, compositions are obtained by uniformly and thoroughly mixing the active ingredient with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, molding the product into the target composition.

Compositions of the present invention suitable for oral administration may be in the form of discrete units, such as capsules, sachets, tablets or lozenges, each of which contains a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid, such as ethanol or glycerin; or as an oil-in-water or water-in-oil emulsion. Such oils may be edible oils, such as, for example, cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural resins such as tragacanth, alginate, gum arabic, dxtran, sodium carboxymethyl cellulose, gelatin, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carbomerprolide and polycarbylprolide. Active ingredients may also be administered as a bolus, electuary or paste.

Tablets may be prepared by compressing or molding the active ingredient, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable device the active ingredient (s) in a free-flowing form, such as powder or granules, optionally mixed with a binder, such as, for example, lactose, glucose, starch, gelatin, gum arabic, tragacanth gum , sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, waxes and the like; a lubricant such as, for example, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrant, such as, for example, starch, methyl cellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, crospovidone or the like, or a dispersant, such as polysorbate 80. Molded tablets can be prepared by molding in a suitable device a mixture powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be formulated as suppositories in which the compound of the present invention is mixed with low melting soluble or water insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or esters of fatty acids and polyethylene glycols, while elixirs may be obtained using myristyl palmitate.

Compositions suitable for parenteral administration typically include sterile oily or aqueous preparations of the active ingredients, which are preferably isotonic with the blood of the recipient, for example, isotonic saline solution, isotonic glucose solution or buffer solution. Typically, the composition can be sterilized, for example, by filtration through a filter that traps bacteria, adding a sterilizing agent to the composition, irradiating or heating the composition. Liposomal compositions as disclosed, for example, in Encyclopedia of Pharmaceutical Technology, vol. 9.1994 are also suitable for parenteral administration.

Alternatively, the compound of formula I can be presented as a sterile solid preparation, for example a lyophilized powder, which is readily soluble in a sterile solvent immediately before use.

Percutaneous compositions can be presented in the form of a patch or applicator.

Compositions suitable for ophthalmic administration may be presented as a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example, as a suspension of microcrystals in water. For ophthalmic administration of the active ingredient, liposome compositions or biodegradable polymer systems can also be used, for example, as disclosed in Encyclopedia of Pharmaceutical Technology. vol. 2.1989.

Compositions suitable for topical or ophthalmic administration include liquid or semi-liquid preparations, such as liniment, lotions, gels, applicants, oil-in-water emulsions, or water-in-oil emulsions, such as creams, ointments, or pastes; or solutions or suspensions, such as drops.

Compositions suitable for nasal or buccal administration include powder compositions, self-propelled compositions, and spray compositions such as aerosols and nebulizers.

In addition to the above ingredients, compositions based on a compound of formula I may include one or more additional ingredients, such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives, for example methyl hydroxybenzoate (including antioxidants), emulsifying agents, etc. .P.

In systemic treatment using the present invention, daily doses of a compound of formula I are administered in the amount of 0.001-500 mg per kilogram of body weight, preferably 0.002-100 mg / kg of mammalian body weight, for example 0.003-20 mg / kg or 0.003-5 mg / kg as a rule, in accordance with the daily dose for an adult, comprising from 0.01 to 37000 mg. However, the present invention also provides compounds and compositions intended for administration at longer intervals, for example, every week, every three weeks or every month. In the local treatment of dermatological disorders, ointments, creams or lotions containing 0.1-750 mg / g, preferably 0.1-500 mg / g, for example 0.1-200 mg / g, compounds of the formula I are administered. Ophthalmologists administer ointments, drops or gels containing 0.1-750 mg / g, preferably 0.1-500 mg / g, for example 0.1-200 mg / g of the compound of formula I. Oral compositions are preferably obtained in the form of tablets, capsules or drops containing 0.07-1000 mg, preferably 0.1-500 mg, of a compound of formula I in a dosage form.

It was found that derivatives of cyanoguanidine are able to modulate the activity of IκB kinase (hereinafter, the abbreviation IKK is used). By modulating IKK activity in cells, the level of activated NFκB can be regulated. Therefore, it is believed that such cyanoguanidines can be used to treat proliferative diseases and other conditions that are believed to be related to the level of activated NFκB, for example, inflammation.

NFκB is a member of the family of Rel transcription factors that are ubiquitous in animal cells. Rel proteins can form dimers, the most common of which are designated NFκB. NFκB is a p50 / p65 heterodimer that can activate transcription of genes containing the corresponding κB binding site. In unstimulated cells, the level of NFκB is maintained in the cytoplasm through interaction with proteins that inhibit NFκB, IκBs. In response to cell stimulation with, for example, antiproliferative drugs or ionizing radiation IκB, the kinase complex (IKK) is rapidly activated and phosphorylates two serine residues in the NFκB binding domain of IκB. Phosphorylated IκB is then destroyed by 26S protease, while NFκB is not destroyed and transferred to the nucleus [Wang, Science, 274,784-787,1996, Cusak, Cancer Research, 60,2323-2330,2000; Karin, Immunology. 12,2000,85-98]. Thus, NFκB is always present in the cell, but in unstimulated cells in an unactivated form. After being transferred to the nucleus, NFκB induces, among other things, anti-apoptotic genes c-IAP1, c-IAP2, TRAF1, TRAF2, Bfl-1 / A1, Bcl-X _L and Mn-SOD [Platel, Oncogene, 19, 2000, 4159- 41699], which causes cell resistance to apoptosis. This effect is referred to as the anti-apoptotic effect of NFκB. Thus, antiproliferative drugs and ionizing radiation contribute to the emergence in cells of resistance to influences that make them ineffective. Accordingly, activated NFκB is a key factor ensuring the resistance of, for example, cancer cells to antiproliferative drugs and / or to ionizing radiation. This is further confirmed by the fact that constitutively activated NFκB was found in cells of resistant cancer tumors [Patel, Oncogene, 19, 4159-4169, 2000]. Regardless of a decrease in resistance to any effect, a decrease in the level of activated NFκB in the cell, for example, by suppressing IKK activity, reduces the expression levels of genes encoding anti-apoptotic factors, causing apoptosis in cells [Schwartz, Surgical Oncology, 8, 1999,143 -153].

The role of activated NFκB is not limited to preventing apoptosis. NFκB is also a major activator of genes involved in inflammatory and immunological processes. Activated NFκB induces a gene encoding cyclooxygenase 2 (COX2), which catalyzes the synthesis of pro-inflammatory prostaglandins. In addition, in the later stages of the inflammation process, COX2 catalyzes the synthesis of anti-inflammatory cyclopentenone prostaglandins. It is also known that COX2 has an antiviral effect, suggesting that NFκB may also be a target in the treatment of inflammatory and viral diseases [Rossi, Nature, 403, 2000, 103-108]. NFκB is also responsible for the transcriptional regulation of genes that play an important role in many other vital cellular processes. For example, NFκB regulates genes encoding cytokines and growth factors, adhesion factors, acute phase agents, receptors, and chemoattractants [Schwartz, Surgical Oncology, 8, 1999,143.153]. This is further confirmed by Rossi in Nature, 403, 103-108, 2000, where he discloses that another type of compound, namely cyclopentenone prostaglandins, inhibits IκB kinase and that this makes cyclopentenone prostaglandins potentially useful for treating cancer, inflammation and viral infections. IκB non-covalently binds to NFκB and disguises its nuclear translocation signal, thus preventing its movement into the nucleus. Various IκBs have been identified and, for example, IκBα and IκBβ are expressed in most cells where they bind to Rel proteins p65, i.e., NFκB. Different IκB are phosphorylated under the influence of various factors, providing activation of NFκB in response to different stimuli.

The IκB kinase complex consists of three subunits, namely IKKα, IKKβ and IKKγ, with a total molecular weight of 900 kDa. IKKα and IKKβ both have IκB kinase activity and phosphorylate IκB, while IKKγ is a regulatory subunit. IKKα is a 85 kDa protein, and IKKβ is a 87 kDa protein, and these two subunits have a high degree of homology. Although both IKKα and IKKβ are catalytically active, it was unexpectedly found that only IKKβ is necessary for IKK phosphorylation of IκB.

As described above, regulating the level of activated NFκB by suppressing IKK activity can be used as a therapeutic measure in the treatment of proliferative diseases, for example, cancers and especially resistant forms of cancer. Inhibition of IKK activity can also be used to treat inflammatory or viral diseases. Regulation of IKK activity can be either single agent therapy, or it can be part of a combination treatment.

Apoptosis is a genetically encoded program of cell death, characterized by the "active decision" of the cell to die, adopted on the basis of information received from the environment, history of its development, etc. Unlike cells undergoing necrosis, cells entering apoptosis are often able to survive, but prefer to die for the good of the whole organism. Apoptosis also differs from necrosis in that necrosis is often associated with tissue trauma and cell damage, while cells following apoptosis are destroyed from the inside in a controlled manner [Tran, Science and Medicine, 6, 18-27, 1999; Williams, Trends Cell Biol., 2, 263-267, 1992].

In a preferred embodiment, the invention provides pharmaceutical compositions comprising a compound of formula I in combination with one or more other pharmacologically active compounds used to treat proliferative diseases. Examples of compounds used to treat proliferative diseases that can be used with the compounds of the present invention include S-triazine derivatives, such as altretamine; enzymes such as asparaginase; antibiotic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, epirubicin and plicamycin; alkylating agents such as busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine and thiotepa; antimetabolites such as cladribine, cytarabine, phloxuridine, fludarabine, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, gemcitabine, pentostatin and thioguanine; antimitotic agents such as etoposide, paclitaxel, teniposide, vinblastine, vinorelbine and vincristine; hormonal agents, for example aromatase inhibitors, such as aminoglutethimide, corticosteroids, such as dexamethasone and prednisone, as well as luteinizing hormone releasing factor (LH-RH - luteinizing hormone releasing hormone); antiestrogens such as tamoxifen, formestane and letrozole; antiandrogens such as flutamine; biological response modulators, for example lymphokines, such as aldesleukin and other interleukins; interferon, such as interferon-α; growth factors such as erythropoietin, filgrastim and sagramostim; differentiating agents, such as vitamin D derivatives, for example, seocalcitol, and fully trans retinoic acid; immunoregulators such as levamisole; as well as monoclonal antibodies, tumor necrosis factor and angiogenesis inhibitors. Finally, ionizing radiation, although not well defined as a compound, is widely used to treat tumor diseases and can be combined with the compounds of the present invention. Due to the fact that patients receiving antitumor treatment usually experience severe side effects, it is often desirable to administer medications that are not antitumor in themselves, but which help to relieve side effects to a sufficient extent. Such compounds include amifostine, leucovorin, and mesna.

In particular, antiproliferative compounds such as paclitaxel, fluorouracil, etoposide, cyclophospamide, cisplatin, carboplatin, vincristine, gemcitabine, vinorelbine, chlorambucil, doxorubicin, melphalan and seocalcitol are successfully used in the combined compositions of the present invention.

It is contemplated that the combination composition of the present invention may be provided as mixtures of compounds or as separate compounds intended for simultaneous or sequential administration. The choice of time intervals in sequential administration can be made by an experienced doctor or veterinarian.

In particular, proliferative diseases or conditions to be treated using the method of the present invention include a number of cancer and tumor diseases or conditions, such as leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphatic leukemia, myelodysplasia, multiple myeloma, Hodgkin's disease or not - Hodgkin's lymphoma, small cell or non-small cell lung carcinoma, cancer of the stomach, intestines or colon and rectum, cancer of the prostate, ovary or breast, head cancer s, brain or neck, cancer of the urinary tract, kidney or cancer of the bladder, malignant melanoma, cancer of the liver, cancer of the uterus or pancreas.

This invention also relates to the use of a compound of formula I, optionally together with the other antitumor compounds described above, in the manufacture of medicaments. In particular, if it is intended to use said medicament for the treatment of proliferative diseases, for example cancers, such as those described above.

METHODS FOR PRODUCING

The values of chemical shifts for the ¹ H nuclear magnetic resonance (NMR) spectra (300 MHz) and ¹³ C NMR (75.6 MHz) lead to internal standards trimethylsilane (δ = 0.00), chloroform (δ = 7.25) or deuteriochloroform (δ = 76.81 for ¹³ C NMR). The value of the multiplet, either specific (singlet (s), doublet (d), triplet (t), quartet (q)), or indefinite (wide (width)), is given at an approximate midpoint if the interval is not defined. Anhydrous organic solvents are used.

Production Method 1

3- [6- (N-tert-butoxycarbonylamino) -1-hexyloxy] pyridine

3-Hydroxypyridine (262 mg) was added to a suspension of 60% sodium hydride (128 mg) in N, N-dimethylformamide (5 ml) and the mixture was stirred for 30 minutes at 60 ° C. After cooling on ice, a solution of N- (tert-butoxycarbonyl) -6-bromohexylamine (770 mg) (Helv. Chim. Acta 76 891 (1993) in N, N-dimethylformamide (3 ml) was added dropwise and stirring was continued overnight at room temperature. Water and ice are added and the mixture is extracted three times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, dried and evaporated to give a yellow oil, which is then purified by silica gel chromatography using diethyl ether as an eluent to obtain the desired compound in colorless about oil.

¹ H NMR (CDCl ₃ ) δ = 8.29 (br s, 1H), 8.20 (m, 1H), 7.18 (m, 2H), 4.53 (br s, 1H), 4 00 (t, 2H), 3.13 (q, 2H), 1.80 (m, 2H), 1.44 (s, 9H), 1.60-1.30 (m, 6H)

The method of obtaining 2

3- [6-amino-1-hexyloxy] pyridine hydrochloride

3- [6- (N-tert-Butoxycarbonylamino) -1-hexyloxy] pyridine (180 mg) was treated with a large excess of hydrogen chloride in diethyl ether with stirring for 45 minutes and then evaporated in vacuo. Triturated with diethyl ether, decanted and evaporated to give the title compound as a colorless powder.

¹ H NMR (DMSO) δ = 8.64 (d, 1H), 8.46 (d, 1H), 8.08 (m, 1H), 8.08 (br s, 3H), 7.88 ( dd, 1H), 4.20 (t, 2H), 2.74 (m, 2H), 1.76 (m, 2H), 1.59 (m, 2H), 1.41 (m, 4H)

The method of obtaining 3

3- [6-amino-1-hexyloxy] pyridine

A solution of 3- [6-amino-1-hexyloxy] pyridine hydrochloride in water was strongly alkalinized with sodium hydroxide and extracted twice with chloroform. The organic phase is dried and evaporated in vacuo to give an oil, which is used in the next step without further purification.

The method of obtaining 4

1- [6- (N-tert-butoxycarbonylamino) -1-hexyl] imidazole

Imidazole (70 mg) and 1.4M sodium methoxide (1 ml) are added to N, N-dimethylformamide (3 ml) and the mixture is stirred at room temperature for 30 minutes. A solution of N- (tert-butoxycarbonyl) -6-bromohexylamine (280 mg) in N, N-dimethylformamide (1 ml) was added and, after heating at 80-90 ° C for 30 minutes, stirring was continued overnight at room temperature. After evaporation in vacuo, it was stirred with acetone and filtered to give a filtrate, which, after evaporation, was purified by silica gel chromatography using ethyl acetate / methanol (4: 1) as an eluent, to give the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ = 7.46 (t, 1H), 7.05 (t, 1H), 6.90 (t, 1H), 4.60 (br s, 1H), 3.92 (t, 2H), 3.08 (q, 2H), 1.76 (m, 2H), 1.44 (s, 9H), 1.44 (m, 2H), 1.32 (m, 4H )

The method of obtaining 5

1- (6-amino-1-hexyl) imidazole hydrochloride

It is prepared as described in Production Method 2, but 3- [6- (N-tert-butoxycarbonylamino) -1-hexyloxy] pyridine is replaced by 1- [6- (N-tert-butoxycarbonylamino) -1-hexyl] imidazole. Colorless crystals.

¹ H NMR (DMSO) δ = 14.99 (br s, 1H), 9.31 (t, 1H), 8.23 (br s, 3H), 7.86 (t, 1H), 7, 71 (t, 1H), 4.22 (t, 2H), 2.73 (m, 2H), 1.81 (m, 2H), 1.58 (m, 2H), 1.36 (m, 2H) ), 1.23 (m, 2H)

The method of obtaining 6

1- (6-amino-1-hexyl) imidazole

Prepared as described in Production Method 3, but 3- [6-amino-1-hexyloxy] pyridine hydrochloride was replaced with 1- (6-amino-1-hexyl) imidazole hydrochloride. Colorless oil.

The method of obtaining 7

2- [6 (N-tert-butoxycarbonylamino) -1-hexyloxy] quinoline

This compound is prepared as described in Production Method 1, but 3-hydroxypyridine is replaced with 2-hydroxyquinoline. The crude product was purified by silica gel chromatography with ethyl acetate as an eluent to give the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ = 7.66 (d, 1H), 7.56 (m, 2H), 7.35 (brd, 1H), 7.22 (m, 1H), 6.70 (d, 1H), 4.57 (br s, 1H), 4.28 (m, 2H), 3.12 (m, 2H), 1.75 (m, 2H), 1.44 (s, 9H), 1.55-1.35 (m, 6H)

The method of obtaining 8

2- (6-amino-1-hexyloxy) quinoline

2- [6- (N-tert-butoxycarbonylamino) -1-hexyloxy] quinoline (480 mg) was treated with a large excess of hydrogen chloride in diethyl ether with stirring for 1 hour at room temperature. The crystalline product was isolated by filtration and redissolved in water, after which the solution was strongly alkalinized with sodium hydroxide and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to give the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ = 7.66 (d, 1H), 7.56 (m, 2H), 7.36 (m, 1H), 7.22 (m, 1H), 6.69 (d , 1H), 4.29 (m, 2H), 2.70 (t, 2H), 1.76 (m, 2H), 1.65 (br s, 2H), 1.45 (m, 6H)

Example 1

N- [6- (3-pyridyloxy) -1-hexyl] -N'-cyano-N '' - (4-pyridyl) guanidine

A mixture of 3- [6-amino-1-hexyloxy] pyridine (150 mg), S-methyl-N-cyano-N'-4-pyridylisothiourea (123 mg), triethylamine (0.18 ml), 4- (N, N-dimethylamino) pyridine (3.5 mg) and pyridine (5 ml) were stirred overnight at 60 ° C. After cooling to room temperature, pyridine was removed by evaporation twice in vacuo with toluene, and the residue was partitioned between water and ethyl acetate. The organic phase was dried and evaporated to give a crude product, which was purified by silica gel chromatography using ethyl acetate / methanol / aqueous ammonia (40: 10: 2.5) as an eluent. Pure fractions were combined and evaporated to give the title compound, which was crystallized from ethyl acetate.

¹ H NMR (DMSO) δ = 9.40 (broad s, 1H), 8.38 (broad d, 2H), 8.28 (d, 1H), 8.15 (dd, 1H), 7, 86 (br t, 1H), 7.37 (m, 1H), 7.31 (dd, 1H), 7.22 (br s, 2H), 4.04 (t, 2H), 3.28 (q, 2H), 1.74 (m, 2H), 1.56 (m, 2H), 1.40 (m, 4H)

Example 2

N- [6- (1-imidazolyl) -1-hexyl-N'-cyano-N '' - (4-pyridyl) guanidine

This compound is prepared as described in Example 1, but 3- [6-amino-1-hexyloxy] pyridine is replaced by 1- (6-amino-1-hexyl) imidazole

¹ H NMR (DMSO) δ = 9.35 (br s, 1H), 8.39 (m, 2H), 7.86 (br t, 1H), 7.61 (t, 1H), 7, 22 (m, 2H), 7.14 (t, 1H), 6.88 (t, 1H), 3.94 (t, 2H), 3.26 (q, 2H), 1.70 (m, 2H), 1.52 (m, 2H), 1.27 (m, 4H)

Example 3

N- [6- (2-Quinolyloxy) -1-hexyl] -N'-cyano-N '' - (4-pyridyl) guanidine

Obtained as described in example 1, but 3- [6-amino-1-hexyloxy] pyridine is replaced by 2- (6-amino-l-hexyloxy) quinoline.

¹ H NMR (DMSO) δ = 9.39 (br s, 1H), 8.38 (m, 2H), 7.90 (d, 1H), 7.87 (br t, 1H), 7, 73 (m, 1H), 7.62 (m, 1H), 7.55 (broad d, 1H), 7.30-7.10 (m, 3H), 6.61 (d, 1H), 4 23 (m, 2H), 3.27 (q, 2H), 1.61 (m, 2H), 1.54 (m, 2H), 1.39 (m, 4H)

Example 4

N- [6- (3-Pyridyl) -1-hexyl] -N'-cyano-N '' - (4-pyridyl) guanidine

Receive as described in example 1, but 3- [6-amino-1-hexyloxy] pyridine is replaced by 3- (6-amino-1-hexyl) pyridine.

¹³ C NMR (DMSO) δ = 157.0, 150.1, 149.5, 146.9, 145.8, 137.4, 135.6, 123.3, 116.4, 114.5, 41, 7, 31.9, 30.4, 28.5, 28.1, 25.8

Example 5

N- [6- (3-Quinolyl) -1-hexyl] -N'-cyano-N '' - (4-pyridyl) guanidine

Obtained as described in example 1, but 3- [6-amino-1-hexyloxy] pyridine is replaced by 3- (6-amino-1-hexyl) quinoline.

¹³ C NMR (DMSO) δ = 157.0, 151.9, 150.1, 146.2, 145.7, 135.0, 133.7, 128.5, 128.4, 127.7, 127, 5, 126.4, 116.4, 114.5, 41.7, 32.1, 30.3, 28.5, 28.1, 25.8

Example 6

N- [6- (5-pyrimidinyl) -1-hexyl] -N'-cyano-N '' - (4-pyridyl) guanidine

Receive as described in example 1, but 3- [6-amino-1-hexyloxy] pyridine is replaced by 5- (6-amino-1-hexyl) pyrimidine.

¹³ C NMR (DMSO) δ = 157.1, 156.6, 156.2, 149.9, 145.5, 135.3, 116.3, 114.4, 41.7, 29.9, 29, 2, 28.4, 28.0, 25.7

Example 7

A pharmaceutical composition in the form of a tablet 0.1 mg of the compound of Example 1, 300 mg of glucose, 6.2 mg of lactose, 0.6 mg of magnesium stearate, 30 mg of starch are thoroughly mixed and pressed in a suitable tablet forming apparatus.

Pharmacological activity

Tests were conducted by evaluating the proliferation of small cell lung carcinoma cells (NYH). The experimental technique and technique correspond to the traditional one used in similar studies.

In vitro test results evaluating cell proliferation of small cell lung carcinoma of a person (NYH).

Compound NYH / IC ₅₀ (nM) Example No. 3 of the present invention 0.02 Example No. 4 of the present invention 0.6 Example No. 5 of the present invention 0.08

As can be seen from the table, these compounds are able to inhibit the proliferation of cancer cells in vitro at low concentrations.

Claims (9)

1. The compound of formula I

where R1 is hydrogen; X is a linear or branched, saturated or unsaturated C _1-12 hydrocarbon diradical; Y is a bond or O; Z is a 5-10 membered aromatic heterocyclic radical optionally substituted with hydroxy; with the proviso that R1 is not attached to the nitrogen atom in the pyridyl ring; and its pharmaceutically acceptable salts. 2. The compound according to claim 1, where R1 is hydrogen; X is a linear C _4-12 hydrocarbon diradical; Y is a bond or O; Z is a 5-10 membered aromatic heterocyclic radical with 1 to 3 nitrogen atoms. 3. The compound according to claim 1, where R1 is hydrogen; X is a linear saturated C _5-10 hydrocarbon diradical; Y is O; Z is a 5-10 membered aromatic heterocyclic radical with 1 to 3 nitrogen atoms. 4. The compound according to claim 1, where Z is pyridyl, imidazolyl, quinolyl or pyrimidinyl. 5. The compound according to claim 1, selected from the group consisting of N- [6- (3-pyridyloxy) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine; N- [6- (1-imidazolyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine; N- [6- (2-Quinolyloxy) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine; N- [6- (3-pyridyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine; N- [6- (3-Quinolyl) -1-hexyl] -N'-cyano-N "- (4-pyridyl) guanidine; N- [6- (5-pyrimidinyl) -1-hexyl] -N'-cyano-N "- (4-pyrididyl) guanidine. 6. The compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of proliferative diseases. 7. A pharmaceutical composition having antiproliferative activity, comprising a compound according to any one of claims 1 to 5, together with pharmaceutically acceptable excipients. 8. The composition according to claim 7 in the form of a single dosage form. 9. The use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of proliferative diseases.